Volume 7, Number 2, June 2006

PAPERGenetic Clamping of Renin Gene Expression Induces Hypertension and Elevation of Intrarenal Ang II Levels of Graded Severity in Cyp1a1-Ren2 Transgenic Rats
Kenneth D Mitchell, Stuart J Bagatell, Chad S Miller, Cynthia R Mouton, Dale M Seth, John J Mullins

Introduction. Transgenic rats with inducible angiotensin II (Ang II)-dependent hypertension (strain name: TGR[Cyp1a1-Ren2]) were generated by inserting the mouse Ren2 renin gene, fused to the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the rat. The present study was performed to characterise the changes in plasma and kidney tissue Ang II levels and in renal haemodynamic function in Cyp1a1-Ren2 rats following induction of either slowly developing or malignant hypertension in these transgenic rats.
Materials and Methods. Arterial blood pressure (BP) and renal haemodynamics and excretory function were measured in pentobarbital sodium-anaesthetised Cyp1a1- Ren2 rats fed a normal diet containing either a low dose (0.15%, w/w for 14–15 days) or high dose (0.3%, w/w for 11–12 days) of the aryl hydrocarbon indole-3-carbinol (I3C) to induce slowly developing and malignant hypertension, respectively. In parallel experiments, arterial blood samples and kidneys were harvested for measurement of Ang II levels by radioimmunoassay.
Results. Dietary I3C increased plasma renin activity (PRA), plasma Ang II levels, and arterial BP in a dose-dependent manner. Induction of different fixed levels of renin gene expression and PRA produced hypertensive phenotypes of varying severity with rats developing either mild or malignant forms of hypertensive disease. Administration of I3C, at a dose of 0.15% (w/w), induced a slowly developing form of hypertension whereas administration of a higher dose (0.3%) induced a more rapidly developing hypertension and the clinical manifestations of malignant hypertension including severe weight loss. Both hypertensive phenotypes were characterised by reduced renal plasma flow, increased filtration fraction, elevated PRA, and increased plasma and intrarenal Ang II levels. These I3C-induced changes in renal haemodynamics, PRA and kidney Ang II levels were more pronounced in Cyp1a1-Ren2 rats with malignant hypertension. Chronic administration of the AT₁-receptor antagonist, hypertension, the associated changes in renal haemodynamics, and the augmentation of intrarenal Ang II levels.
Conclusions. Activation of AT₁-receptors by Ang II generated as a consequence of induction of the Cyp1a1-Ren2 transgene mediates the increased arterial pressure and the associated reduction of renal haemodynamics and enhancement of intrarenal Ang II levels in hypertensive Cyp1a1-Ren2 transgenic rats.

JRAAS 2006;7:74-86.

PAPERCNP, but not ANP or BNP, Relax Human Isolated Subcutaneous Resistance Arteries by an Action Involving Cyclic GMP and BKCa Channels
Robinder S Garcha, Alun D Hughes

Natriuretic peptides play an important role in sodium regulation and blood pressure (BP) control. We examined the effects of atrial natriuetic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) on human isolated resistance arteries and the mechanisms involved in vasorelaxation. Human subcutaneous resistance arteries were mounted in an isometric myograph and contracted with phenylephrine. CNP, but not ANP or BNP, relaxed arteries in a concentration dependent manner. The action of CNP was unaffected by removal of the endothelium, inhibition of nitric oxide synthase by NG-monomethyl-Larginine or inhibition of soluble guanylate cyclase by 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one. Blockade of cyclic GMPdependent kinase by 8- bromoguanosine- 3’, 5’- cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS) inhibited CNP relaxation. CNP relaxation was also inhibited by high potassium or iberiotoxin, indicating that it was due to opening of BKCa channels. Omapatrilat, a vasopeptidase inhibitor of neutral endopeptidase and angiotensin-converting enzyme, enhanced the effect of CNP and inhibited responses to Ang I. In summary, CNP, but not ANP or BNP, relaxes human resistance arteries by activating cyclic GMP-dependent kinase and BKCa. The effects of CNP are enhanced by vasopeptidase inhibition and this may contribute to the vasodilator effects of these agents in vivo. Since CNP is widely present in endothelium it may play a role in the regulation of peripheral resistance in man in physiological and pathological circumstances.

JRAAS 2006;7:87-91.

PAPERInfluence of Gender and Genetic Variability on Plasma Angiotensin Peptides
Armando Reyes-Engel, Luis Morcillo, Francisco Javier Aranda, Maximiliano Ruiz, Maria Jesús Gaitan, Álvaro Mayor-Olea, Pedro Aranda, Carlos Maria Ferrario

Introduction. We analysed the influence of three polymorphisms of the renin-angiotensin system (RAS) (I/D from angiotensin-converting enzyme [ACE], M235T from angiotensinogen gene [ATG] and A1166C from AT₁ receptors) on plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)].
Materials and Methods. The study population consisted of a homogeneous group of 93 healthy subjects (43 men and 50 women, mean age: 20.67±2.75 years). The mean blood pressure (BP) was 126±7/76±5 (SD) mmHg and the mean body mass index (BMI) was 22.4±2.5 kg/m². Angiotensin peptides were separated by high performance liquid chromatography (HPLC) and quantified by radio immuno assay (RIA). Genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme analysis.
Results. Mean peptide levels were 92.48±102.12 pg/ml for Ang I, 22.35±10 pg/ml for Ang II, and 31.65±27.46 pg/ml for Ang-(1-7). Men had significantly higher levels of Ang-(1-7) (37.76±36.47 pg/ml) than women (26.04±13.98 pg/ml) (p<0.05). Among genotypes of each polymorphism, men with the T allele showed higher Ang- (1-7) levels compared with those with the MM genotype (p<0.05). Genotype analysis in women showed that higher Ang I levels were related with the DD genotype. When both genders were compared according to genotype, higher values of Ang-(1-7) levels and its molar ratios were found in men, and there was significantly greater Ang I levels in DD genotypes in women than men (136.72±112.43 vs. 65.36±46.83 pg/mL).
Conclusions. Significant correlations were found between Ang I and Ang II as well as between Ang II and Ang-(1-7) in the different study group distributions. No correlation was found between levels of Ang I and Ang-(1-7). Certain genotypes exert an influence on angiotensin peptide plasma levels which can only be seen when the population is divided according to gender.

JRAAS 2006;7:92-97.

POPULAR
TOPICPAPEREffects of ACE Inhibition and Angiotensin II Receptor Blockade on Glomerular Basement Membrane Protein Excretion and Charge Selectivity in Type 2 Diabetic Patients
Oguzhan Deyneli, Dilek Yavuz, Ayliz Velioglu, Hasan Cac?na, Nihal Aksoy, Goncagül Haklar, Yavuz Taga, Sema Akal?n

Angiotensin-converting enzyme (ACE) inhibitors may reduce urinary albumin excretion (UAE) by decreasing glomerular pressure and increasing glomerular charge selectivity through preservation of glycosaminoglycans. The effect of Angiotensin II antagonism on glomerular charge selectivity remains to be determined. The aim of this study was to compare the effects of an AT₁ blocker losartan and an ACE inhibitor (ACE-I) enalapril on UAE, extracellular matrix proteins, glycosaminoglycan excretion (U_GAG) and red blood cell anionic charge (RBCCh) which are the indirect markers of glomerular basement membrane anionic content in hypertensive Type 2 diabetic patients. Twenty-four patients were randomised into two groups and received either enalapril (5–20 mg/d) or losartan (50–100 mg/d). All parameters were measured at baseline and after six months of treatment. At the end of six months, systolic and diastolic blood pressures (BP), UAE rates, UGAG excretion and RBCCh were significantly and equally reduced in both treatment groups compared with baseline. RBCCh was negatively correlated with UAE (r=-0.57, p<0.0001) and U_GAG excretion (r=-0.57, p<0.0001); UAE was correlated with U_GAG excretion (r=0.58, p<0.0001). In conclusion, enalapril and losartan treatment were equally effective in reducing BP, UAE as well as U_GAG excretion and preserving RBCCh in hypertensive Type 2 diabetic patients. ACE inhibition and AT₁-receptor blockade may have favourable effects on preserving glomerular anionic content in hypertensive diabetic patients.

JRAAS 2006;7:98-103.

POPULAR
TOPICEDITORIAL REVIEWFrom Hypertension to Heart Failure – Are There Better Primary Prevention Strategies?
Peter A Meredith, Jan Östergren

Although in the developed world the incidence of and mortality from coronary heart disease (CHD) and stroke have been declining over the last 15 years, heart failure is increasing in incidence, prevalence and overall mortality, despite advances in the diagnosis and management of the condition. Hypertension, alone or in combination with CHD, precedes the development of heart failure in the majority of both men and women. Whilst there have been improvements in the overall management of hypertension, as reflected in rates of diagnosis, awareness, treatment and control of blood pressure (BP), there are still many patients with hypertension who remain undiagnosed or untreated and of those who do receive treatment many fail to achieve current targets for BP control. Placebo-controlled trials in hypertension, largely based on diuretic and beta-blocker-based regimens, have unequivocally demonstrated that the treatment of hypertension can significantly reduce the incidence of heart failure. Newer treatment strategies offer theoretical and proven practical advantages over established antihypertensive therapy. In particular, AT1-receptor blockers appear to provide benefits beyond BP control and are effective in the treatment of both hypertension and heart failure. Thus, the primary prevention of heart failure in hypertensive patients should be based upon strategies that provide tight and sustained BP control necessitating the use of multiple drugs. However, there is now compelling evidence to suggest that this therapy should include an antihypertensive agent that inhibits the reninangiotensin- aldosterone system (RAAS).

JRAAS 2006;7:64-73.

POPULAR
TOPICCOMMENTARYNew Hypertension Guidelines from the National Institute for Health and Clinical Excellence and the British Hypertension Society
Peter Sever

A joint initiative between the National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society (BHS) has led to the publication of new guidelines for the management of hypertension in the community. Recent trial evidence highlighting the increased incidence of new-onset diabetes in those exposed to beta-blocker-based treatment regimens, with or without diuretics, compared with those based on calcium channel blockers (CCBs) or angiotensin-converting enzyme (ACE-Is) inhibitors has led to a recommendation that in the uncomplicated patient, beta-blockers are no longer considered suitable options for first-line therapy. Together with mounting evidence that age and ethnicity dictate blood pressure (BP) responsiveness to different classes of antihypertensive drugs, the ACD algorithm is now proposed (formerly ABCD), with ACE inhibitors (ACE-Is) (or angiotensin receptor blockers [ARBs] when ACE-Is are poorly tolerated) preferred in younger patients and CCBs or diuretics preferred for older patients and in black patients of any age. Pathophysiological considerations have influenced proposals for combination therapies with CCBs or diuretics added to ACE-Is in younger patients and vice versa in older patients. Health economic analyses have clearly indicated the cost effectiveness of CCBs which are now elevated to equal standing with diuretics in older patients.

JRAAS 2006;7:61-63.

RENIN REPORTSpotlight on Renin: Intrarenal renin-angiotensin system – important player of the local milieu
Hermann Haller, Joon-Keun Park, Carsten Lindschau, Matthias Meyer, Jan Menne

JRAAS 2006;7:122-126.

RENIN REPORTSpotlight on Renin: Renin Academy hosts Topical Workshop session at ESH 2006

JRAAS 2006;7:126-128.

POPULAR
TOPICSYMPOSIUMAngiotensin-Converting Enzyme Inhibitors Versus Angiotensin Receptor Blockers - A mini-symposium held at the British Hypertension Society Meeting, September 2005

JRAAS 2006;7:104-121.